OBJECTIVE:To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.
METHODS:A ...prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors.
RESULTS:We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinsonʼs Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001).
CONCLUSIONS:Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.
Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense ...oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.
This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated
with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.
Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months;
= 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (
= 22;
= 0.001) and 17.1 months at the highest exposure (
= 10;
= 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months;
= 0.044). Stupp-eligible patients with methylated O
-methylguanine-DNA methyltransferase promoter (
= 10) demonstrated median PFS of 38.4 months (
= 0.0008). Evidence of immune activation was noted.
IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Abstract
Background: We evaluated an autologous cell vaccine, a combination of GBM tumor cells and an antisense molecule against insulin-like growth factor type 1 receptor DNA/mRNA (IGF-1R AS ODN), ...in adults with newly diagnosed GBM (NCT02507583).
Methods: Tumor cells collected during resection were treated ex vivo with IGF-1R AS ODN, encapsulated in biodiffusion chambers with IGF-1R AS ODN, irradiated, then implanted in an abdominal acceptor site on the first post-operative day. Four vaccine exposures were evaluated: lowest (10 chambers implanted for 24 hours); lower (10 / 48 hours); higher (20 / 24 hours); and highest (20 / 48 hours). Standard of care (SOC; ie, radiotherapy and temozolomide) was initiated after 4-6 weeks. Randomization was halted after patient 23 and subsequent patients received the highest exposure. Evaluation of safety and tumor responses were the primary and secondary objectives, respectively. Exploratory objectives included assessment of progression-free survival (PFS) and overall survival (OS). The SOC comparator group was an antecedent cohort of 35 newly diagnosed, GBM patients treated at the same center.
Results: Thirty-three patients were enrolled between September 1, 2015 and March 1, 2018. Six, 5, 5, and 17 patients received the lowest, lower, higher, and highest exposures. Median (range) follow-up was 13 (4-39) months. As of the January 1, 2019 cutoff, no vaccine-related adverse events were observed. Seventeen of 33 (51.5%) remained progression-free, 12 of whom are alive and functioning well. The autologous cell vaccine significantly prolonged PFS and OS vs. SOC (Table). Survival advantages were conferred by the highest exposure to the autologous cell vaccine and good T cell function prior to surgery.
Conclusions: This vaccine was well-tolerated and prolonged PFS and OS when compared with SOC alone.
Table.Survival outcomes in patients receiving vaccine vs. SOC aloneTreatment group2 yr OS estimateMedian OS (mo)p-value v. SOC for OS1 yr PFS estimateMedian PFS estimatep-value v. SOC for PFSVaccine highest dose (N=17)34%21.9.04141%10.4.031Vaccine all (ITT, N=33)31%17.3.01642%9.8.018SOC (n=35)14%12.128%6.9
Citation Format: David W. Andrews, Samantha Garcia, Kevin D. Judy, Larry A. Harshyne, Sanjana Govindarajan, Lawrence Kenyon, Kiran Talekar, Adam Flanders, Kofi-Buaku Atsina, Lyndon Kim, Nina L. Martinez, Wenyin Shi, Maria Werner-Wasik, Mikhail Prosniak, Mark T. Curtis, Rhonda Kean, Emily Bongiorno, Sami Sauma, Kara Pigott, Charles B. Scott, D Craig Hooper. Results of a Phase Ib trial of an autologous cell vaccine for newly diagnosed glioblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT038.
Spatial motor-intentional "Aiming" bias is a dysfunction in initiation/execution of motor-intentional behavior, resulting in hypokinetic and hypometric leftward movements. Aiming bias may contribute ...to posture, balance, and movement problems and uniquely account for disability in post-stroke spatial neglect. Body movement may modify and even worsen Aiming errors, but therapy techniques, such as visual scanning training, do not take this into account. Here, we evaluated (1) whether instructing neglect patients to move midline body parts improves their ability to explore left space and (2) whether this has a different impact on different patients. A 68-year-old woman with spatial neglect after a right basal ganglia infarct had difficulty orienting to and identifying left-sided objects. She was prompted with four instructions: "look to the left," "point with your nose to the left," "point with your right hand to the left," and "stick out your tongue and point it to the left." She oriented leftward dramatically better when pointing with the tongue/nose, than she did when pointing with the hand. We then tested nine more consecutive patients with spatial neglect using the same instructions. Only four of them made any orienting errors. Only one patient made >50% errors when pointing with the hand, and she did not benefit from pointing with the tongue/nose. We observed that pointing with the tongue could facilitate left-sided orientation in a stroke survivor with spatial neglect. If midline structures are represented more bilaterally, they may be less affected by Aiming bias. Alternatively, moving the body midline may be more permissive for leftward orienting than moving right body parts. We were not able to replicate this effect in another patient; we suspect that the magnitude of this effect may depend upon the degree to which patients have directional akinesia, spatial Where deficits, or cerebellar/frontal cortical lesions. Future research could examine these hypotheses.
Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical ...trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14
monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E
remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE
, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.
Abstract
Introduction: We present a novel autologous cell vaccine therapy designed to treat patients with newly diagnosed glioblastoma (Trial Registration: IND 14379, NCT01550523).
Methods: This ...phase 1b trial has a phase 2 design with 4 randomized vaccine dose cohorts in 33 patients with the objective being safety assessment but also including clinical, radiographic, and immune analyses. Eligibility criteria included age > 18 and Karnofsky score of > 60; neither bihemispheric disease nor extent of resection were exclusion criteria but autoimmune diseases were. During craniotomy for tumor resection, if frozen section confirmed GBM, incisions were made in the lower abdomen through the rectus sheath and pockets created between the sheath and the muscle and the wounds closed with a temporary three-layer closure. Tumor resection involved an aspirator that collected morselized viable tumor tissue in sterile traps. The tissue was processed by overnight culture with 0.2 mg of an IGF-1R antisense oligodeoxynucleotide/gm. The next (first postoperative) day, treated tumor cells were harvested, encapsulated in either ten or twenty small biodiffusion chambers along with 4 micrograms of the IGF-1R antisense, irradiated and then implanted at bedside in the abdominal acceptor sites as previously described (1). Chambers were explanted 24 or 48 hours later, depending on randomization. Standard of care according to Stupp (2) was initiated at 6 weeks. Studies included 3T MRI imaging and analysis of serial blood samples for T cell function and cytokine levels. Disease progression was assessed using RANO (3) and iRANO (4) criteria with a data cutoff of March 1 (N=30) used for this analysis.
Results: The trial opened September 1, 2015 and completed accrual on March 1, 2018. A midpoint interim analysis revealed significantly more robust cytokine responses at the highest vaccine dose. Randomization was therefore stopped at subject 23 and amended to treat using only the highest dose. Progression-free survival (PFS) was compared to three historic SOC comparators (Stupp 2, Kong 5, and an antecedent cohort of 37 consecutive patients treated with SOC at our institution TJUH). PFS was significantly improved at 10.5 mo v. SOC comparators: 6.9 mo (Stupp, p = .003), 5.3 mo (Kong, p = .002) and 7 mo (TJUH, p = .013). Seventy-five percent of the 14 patients in the highest-dose cohort had robust proinflammatory and early evidence of sustained immune reactivity associated with tumor regression or no recurrence after surgery.
Conclusion: These data reflect a therapeutic benefit defined as significant improvement in PFS without increased safety risk compared to three different SOC cohorts. Since GBM remains one of the most challenging solid tumors, this treatment design invites investigator collaboration in a multicenter phase 2 trial.
References: 1. Andrew et al. J Clin Oncol 19:2189-2200; 2. Stupp et al. NEJM 352:987-96; 3. Wen et al. J Clin. Oncol 28:1963-72; 4. Okada et al. Lancet Oncol 16:534-42; 5. Kong et al. Oncotarget 8:7003-13.
Citation Format: Kevin D. Judy, David W. Andrews, Larry Harshyne, Lawrence Kenyon, Kiran Talekar, Kofi-Buaku Atsina, Lyndon Kim, Wenyin Shi, Maria Werner-Wasik, Rhonda Kean, Samantha Garcia, Kara Pigott, Charles B. Scott, D. Craig Hooper. Phase 1b/2 prospective randomized trial of four autologous cell vaccine dose cohorts for initial treatment of glioblastoma abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B71.
Cases of a novel coronavirus were first reported in Wuhan, Hubei province, China, in December 2019 and have since spread across the world. Epidemiological studies have indicated human-to-human ...transmission in China and elsewhere. To aid the analysis and tracking of the COVID-19 epidemic we collected and curated individual-level data from national, provincial, and municipal health reports, as well as additional information from online reports. All data are geo-coded and, where available, include symptoms, key dates (date of onset, admission, and confirmation), and travel history. The generation of detailed, real-time, and robust data for emerging disease outbreaks is important and can help to generate robust evidence that will support and inform public health decision making.
Monkeypox virus was first documented in humans in the 1970s and outbreaks have been reported in many countries, with most cases restricted to endemic areas.1 In early May, 2022, monkeypox cases were ...reported in the UK, Spain, and elsewhere in Europe (figure, appendix).2 The pattern of geographical dispersal was much larger compared with past outbreaks that were more localised and occurred often in under-resourced communities.3 The size of the outbreak clusters is growing each day, as is the geographical spread across Europe and North America. WHO convened a meeting of experts and technical advisory groups on May 20, 2022,4 to investigate the causes of the outbreak and have released updated guidance on surveillance, case investigation, and contact tracing.5 The reason for the outbreak having a broader geographical reach is being investigated by the international and national public health community and the research community, contributing to a finer scale understanding of the outbreak dynamics. ...where available, we added information on age (aggregated into age ranges, with a minimum range of 5 years), gender, dates of symptom onset and laboratory confirmation, symptoms, locations (aggregated to the state level), travel history, and additional metadata defined by WHO.5 Data are compiled from verified sources, including reports from governments and public health organisations and news media reporting of health official statements.
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